Open AccessStatins Reduce Thoracic Aortic Aneurysm Growth in Marfan Syndrome Mice via Inhibition of the Ras‐Induced ERK (Extracellular Signal‐Regulated Kinase) Signaling Pathway
Author(s) -
Sato Tetsuya,
Arakawa Mamoru,
Tashima Yasushi,
Tsuboi Eitoshi,
Burdon Grayson,
Trojan Jeffrey,
Koyano Tiffany,
Youn YoungNam,
Penov Kiril,
Pedroza Albert J.,
Shabazzi Mohammad,
Palmon Itai,
Nguyen Marie Noel,
Connolly Andrew J.,
Yamaguchi Atsushi,
Fischbein Michael P.
Publication year - 2018
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.118.008543
Subject(s) - medicine , mapk/erk pathway , pravastatin , signal transduction , rho kinase inhibitor , kinase , statin , phosphorylation , marfan syndrome , protein kinase a , endocrinology , pharmacology , cancer research , rho associated protein kinase , microbiology and biotechnology , biology , cholesterol
Background Statins reduce aneurysm growth in mouse models of Marfan syndrome, although the mechanism is unknown. In addition to reducing cholesterol, statins block farnesylation and geranylgeranylation, which participate in membrane‐bound G‐protein signaling, including Ras. We dissected the prenylation pathway to define the effect of statins on aneurysm reduction. Methods and Results Fbn1 C1039G/+ mice were treated with (1) pravastatin (HMG‐CoA [3‐hydroxy‐3‐methylglutaryl coenzyme A] reductase inhibitor), (2) manumycin A ( MA ; FPT inhibitor), (3) perillyl alcohol ( GGPT 1 and ‐2 inhibitor), or (4) vehicle control from age 4 to 8 weeks and euthanized at 12 weeks. Histological characterization was performed. Protein analysis was completed on aortic specimens to measure ERK (extracellular signal‐regulated kinase) signaling. In vitro Fbn1 C1039G/+ aortic smooth muscle cells were utilized to measure Ras‐dependent ERK signaling and MMP (matrix metalloproteinase) activity. Pravastatin and MA significantly reduced aneurysm growth compared with vehicle control (n=8 per group). In contrast, PA did not significantly decrease aneurysm size. Histology illustrated reduced elastin breakdown in MA ‐treated mice compared with vehicle control (n=5 per group). Although elevated in control Marfan mice, both phosphorylated c‐Raf and phosphorylated ERK 1/2 were significantly reduced in MA ‐treated mice (4–5 per group). In vitro smooth muscle cell studies confirmed phosphorylated cR af and phosphorylated ERK 1/2 signaling was elevated in Fbn1 C1039G/+ smooth muscle cells (n=5 per group). Fbn1 C1039G/+ smooth muscle cell Ras‐dependent ERK signaling and MMP activity were reduced following MA treatment (n=5 per group). Corroborating in vitro findings, MMP activity was also decreased in pravastatin‐treated mice. Conclusions Aneurysm reduction in Fbn1 C1039G/+ mice following pravastatin and MA treatment was associated with a decrease in Ras‐dependent ERK signaling. MMP activity can be reduced by diminishing Ras signaling.